Anti-hypertensive and cholesterol-lowering fixed-dose combination and method of manufacture

Abstract

Disclosed is a method of manufacturing a cardiovascular fixed-dose combination pharmaceutical dosage form that includes an anti-hypertensive active agent, a cholesterol-lowering active agent, and optionally, an enteric-coated aspirin or platelet inhibitor. The fixed-dose combination is prepared with at least two granulation solutions that are free of citric acid and enhance the aqueous solubility of the cholesterol-lowering agent in fixed-dose combination. The active agents in the resulting dosage form, which is also free of citric acid, have the same strength and release profiles as the same active agents prepared as a single formulation.

We claim: 
     
       1. A method comprising:
 blending a cholesterol-lowering drug and an anti-hypertensive drug in a first granulation solution comprising a preservative to form a first granulated mixture, wherein the first granulation solution does not include a binder; 
 adding a second granulation solution comprising a binder to the first granulated mixture to form a second granulated mixture comprising the cholesterol-lowering drug and the anti-hypertensive drug, wherein aqueous solubility of the cholesterol-lowering drug in the second granulated mixture is enhanced relative to a single formulation of a cholesterol-lowering drug; 
 drying the second granulated mixture to form individual granules comprising a combination of the cholesterol-lowering drug and the anti-hypertensive drug; and 
 forming a pharmaceutical dosage form comprising the individual granules, wherein dissolution of the cholesterol-lowering drug in the pharmaceutical dosage form is ˜100% after 45 minutes. 
 
     
     
       2. The method of  claim 1 , wherein the preservative is selected from the group consisting of parabens, acids and their salts, quaternary ammonium compounds, alcohols, biguanides, phenols, phenolic antioxidants, and combinations thereof. 
     
     
       3. The method of  claim 1 , wherein the preservative is solubilized in a liquid selected from the group consisting of water, ethanol, isopropanol, and combinations thereof. 
     
     
       4. The method of  claim 1 , wherein the first granulation solution comprises butylated-hydroxy-anisole (BHA) solubilized in ethanol. 
     
     
       5. The method of  claim 1 , wherein the binder is selected from the group consisting of saccharides, polysaccharides and derivatives, sugar alcohols, proteins, synthetic polymers, and combinations thereof. 
     
     
       6. The method of  claim 1 , wherein the binder is solubilized in a liquid selected from the group consisting of water, ethanol, isopropanol, and combinations thereof. 
     
     
       7. The method of  claim 1 , wherein the second granulation solution comprises polyvinyl pyrrolidone (PVP) solubilized in a water and ethanol solution. 
     
     
       8. The method of  claim 1 , wherein the first granulation solution, the second granulation solution, and the pharmaceutical dosage form are free of citric acid. 
     
     
       9. The method of  claim 1 , wherein the anti-hypertensive drug is selected from the group consisting of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor inhibitors, and beta blockers. 
     
     
       10. The method of  claim 9 , wherein the ACE inhibitors are selected from the group consisting of benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril, and combinations thereof. 
     
     
       11. The method of  claim 9 , wherein the angiotensin receptor inhibitors are selected from the group consisting of azilsartan, candesartan, eprosartan, irbesartan, telmisartan, valsartan, losartan, olmesartan, entresto, byvalson, and combinations thereof. 
     
     
       12. The method of  claim 9 , wherein the beta blockers are selected from the group consisting of betaxolol, pindolol, acebutolol, atenolol, bisoprolol fumarate, carvedilol, esmolol, labetalol, metoprolol, nadolol, nebivolol, and combinations thereof. 
     
     
       13. The method of  claim 1 , wherein the cholesterol-lowering drug is a statin selected from the group consisting of atorvastatin, fluvastatin, lovastatin, pravastatin, pitavastatin, simvastatin, rosuvastatin, and combinations thereof. 
     
     
       14. The method of  claim 1 , wherein the cholesterol-lowering drug is a non-statin selected from the group consisting of ezetimibe, gemfibrozil, fenofibric acid, lomitapide, and combinations thereof. 
     
     
       15. The method of  claim 1 , wherein the anti-hypertensive drug is an ACE inhibitor and the cholesterol-lowering drug is a statin. 
     
     
       16. The method of  claim 1 , wherein the anti-hypertensive drug is lisinopril and the cholesterol-lowering drug is simvastatin. 
     
     
       17. The method of  claim 1 , wherein the anti-hypertensive drug is present in the pharmaceutical dosage form in a range of 1 mg to 160 mg per unit dose. 
     
     
       18. The method of  claim 1 , where the cholesterol-lowering drug is present in the pharmaceutical dosage form in a range of 1 mg to 160 mg per unit dose. 
     
     
       19. The method of  claim 1 , wherein the pharmaceutical dosage form further comprises enteric coated aspirin or an enteric coated platelet inhibitor. 
     
     
       20. The method of  claim 19 , wherein the enteric coated platelet inhibitor is selected from the group consisting of clopidogrel, ticagrelor, prasugrel, dipyridamole, ticlopidine, eptifibatide, and combinations thereof. 
     
     
       21. The method of  claim 19 , wherein the enteric coated aspirin or the enteric coated platelet inhibitor is in a concentration of 25 mg to 325 mg per unit dose. 
     
     
       22. The method of  claim 19 , wherein the enteric coated aspirin is in a concentration of 81 mg per unit dose. 
     
     
       23. The method of  claim 1 , wherein the pharmaceutical dosage form is a capsule. 
     
     
       24. The method of  claim 23 , wherein the pharmaceutical dosage form further comprises enteric coated aspirin tablets or an enteric coated platelet inhibitor encased within the capsule. 
     
     
       25. The method of  claim 1 , wherein the pharmaceutical dosage form is a tablet. 
     
     
       26. The method of  claim 25 , wherein the tablet comprises a core and an immediate release outer layer, wherein the core of the tablet is enteric coated aspirin and the immediate release outer layer is comprised of the individual granules comprising the anti-hypertensive drug, the cholesterol-lowering drug, or a combination of the anti-hypertensive drug and the cholesterol-lowering drug. 
     
     
       27. The method of  claim 25 , wherein the tablet comprises a core and an immediate release outer layer, wherein the core of the tablet is an enteric coated platelet inhibitor and the immediate release outer layer is comprised of the individual granules comprising the anti-hypertensive drug, the cholesterol-lowering drug, or a combination of the anti-hypertensive drug and the cholesterol-lowering drug. 
     
     
       28. The method of  claim 1 , further comprising administering a single dosage of the pharmaceutical dosage form to an individual in need of an anti-hypertensive drug and a cholesterol-lowering drug once per 24-hour period. 
     
     
       29. A method comprising:
 blending a cholesterol-lowering drug in a first granulation solution comprising butylated-hydroxy-anisole solubilized in ethanol to form a first granulated mixture, wherein the first granulation solution does not include a binder; 
 adding a granulated anti-hypertensive drug to the first granulated mixture to form a second granulated mixture; 
 adding a second granulation solution comprising a binder to the second granulated mixture to form a third granulated mixture comprising the cholesterol-lowering drug and the anti-hypertensive drug, wherein aqueous solubility of the cholesterol-lowering drug in the third granulated mixture is enhanced relative to a single formulation of a cholesterol-lowering drug; 
 drying the third granulated mixture to form individual granules, wherein each of the individual granules contains the cholesterol-lowering drug, the anti-hypertensive drug, or a combination of the cholesterol-lowering drug and the anti-hypertensive drug; and 
 forming a pharmaceutical dosage form comprising the individual granules, wherein the dissolution of the cholesterol-lowering drug in the pharmaceutical dosage form is ˜100% after 45 minutes. 
 
     
     
       30. The method of  claim 29 , wherein the binder is selected from the group consisting of saccharides, polysaccharides and derivatives, sugar alcohols, proteins, synthetic polymers, and combinations thereof. 
     
     
       31. The method of  claim 29 , wherein the binder is solubilized in a liquid selected from the group consisting of water, ethanol, isopropanol, and combinations thereof. 
     
     
       32. The method of  claim 29 , wherein the second granulation solution comprises polyvinyl pyrrolidone (PVP) solubilized in a water and ethanol solution. 
     
     
       33. The method of  claim 29 , wherein the first granulation solution, the second granulation solution, and the pharmaceutical dosage form are free of citric acid. 
     
     
       34. The method of  claim 29 , wherein the anti-hypertensive drug is selected from the group consisting of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor inhibitors, and beta blockers. 
     
     
       35. The method of  claim 34 , wherein the ACE inhibitors are selected from the group consisting of benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril, and combinations thereof. 
     
     
       36. The method of  claim 34 , wherein the angiotensin receptor inhibitors are selected from the group consisting of azilsartan, candesartan, eprosartan, irbesartan, telmisartan, valsartan, losartan, olmesartan, entresto, byvalson, and combinations thereof. 
     
     
       37. The method of  claim 34 , wherein the beta blockers are selected from the group consisting of betaxolol, pindolol, acebutolol, atenolol, bisoprolol fumarate, carvedilol, esmolol, labetalol, metoprolol, nadolol, nebivolol, and combinations thereof. 
     
     
       38. The method of  claim 29 , wherein the cholesterol-lowering drug is a statin selected from the group consisting of atorvastatin, fluvastatin, lovastatin, pravastatin, pitavastatin, simvastatin, rosuvastatin, and combinations thereof. 
     
     
       39. The method of  claim 29 , wherein the cholesterol-lowering drug is a non-statin selected from the group consisting of ezetimibe, gemfibrozil, fenofibric acid, lomitapide, and combinations thereof. 
     
     
       40. The method of  claim 29 , wherein the anti-hypertensive drug is an ACE inhibitor and the cholesterol-lowering drug is a statin. 
     
     
       41. The method of  claim 29 , wherein the anti-hypertensive drug is lisinopril and the cholesterol-lowering drug is simvastatin. 
     
     
       42. The method of  claim 29 , wherein the anti-hypertensive drug is present in the pharmaceutical dosage form in a range of 1 mg to 160 mg per unit dose. 
     
     
       43. The method of  claim 29 , where the cholesterol-lowering drug is present in the pharmaceutical dosage form in a range of 1 mg to 160 mg per unit dose. 
     
     
       44. The method of  claim 29 , wherein the pharmaceutical dosage form further comprises enteric coated aspirin or an enteric coated platelet inhibitor. 
     
     
       45. The method of  claim 44 , wherein the enteric coated platelet inhibitor is selected from the group consisting of clopidogrel, ticagrelor, prasugrel, dipyridamole, ticlopidine, eptifibatide and combinations thereof. 
     
     
       46. The method of  claim 44 , wherein the enteric coated aspirin or the enteric coated platelet inhibitor is in a concentration of 25 mg to 325 mg per unit dose. 
     
     
       47. The method of  claim 44 , wherein the enteric coated aspirin is in a concentration of 81 mg per unit dose. 
     
     
       48. The method of  claim 29 , wherein the pharmaceutical dosage form is a capsule. 
     
     
       49. The method of  claim 48 , wherein the pharmaceutical dosage form further comprises enteric coated aspirin tablets or an enteric coated platelet inhibitor encased within the capsule. 
     
     
       50. The method of  claim 29 , wherein the pharmaceutical dosage form is a tablet. 
     
     
       51. The method of  claim 50 , wherein the tablet comprises a core and an immediate release outer layer, wherein the core of the tablet is enteric coated aspirin and the immediate release outer layer is comprised of the individual granules comprising the anti-hypertensive drug, the cholesterol-lowering drug, or a combination of the anti-hypertensive drug and the cholesterol-lowering drug. 
     
     
       52. The method of  claim 50 , wherein the tablet comprises a core and an immediate release outer layer, wherein the core of the tablet is an enteric coated platelet inhibitor and the immediate release outer layer is comprised of the individual granules comprising the anti-hypertensive drug, the cholesterol-lowering drug, or a combination of the anti-hypertensive drug and the cholesterol-lowering drug. 
     
     
       53. The method of  claim 29 , further comprising administering a single dosage of the pharmaceutical dosage form to an individual in need of an anti-hypertensive drug and a cholesterol-lowering drug once per 24-hour period. 
     
     
       54. A method comprising:
 blending simvastatin and lisinopril in a first granulation solution comprising butylated-hydroxy-anisole (BHA) to form a first granulated mixture, wherein the first granulation solution does not include a binder; 
 adding a second granulation solution comprising a binder to the first granulated mixture to form a second granulated mixture comprising the simvastatin and the lisinopril, wherein aqueous solubility of the simvastatin in the second granulated mixture is enhanced relative to a single formulation of simvastatin; 
 drying the second granulated mixture to form individual granules comprising a combination of the simvastatin and the lisinopril; and 
 forming a pharmaceutical dosage form comprising the individual granules, wherein dissolution of the simvastatin in the pharmaceutical dosage form is ˜100% after 45 minutes. 
 
     
     
       55. The method of  claim 54 , wherein the BHA is solubilized in ethanol. 
     
     
       56. The method of  claim 54 , wherein the binder is selected from the group consisting of saccharides, polysaccharides and derivatives, sugar alcohols, proteins, synthetic polymers, and combinations thereof. 
     
     
       57. The method of  claim 54 , wherein the binder is solubilized in a liquid selected from the group consisting of water, ethanol, isopropanol, and combinations thereof. 
     
     
       58. The method of  claim 54 , wherein the second granulation solution comprises polyvinyl pyrrolidone (PVP) solubilized in a water and ethanol solution. 
     
     
       59. The method of  claim 54 , wherein the first granulation solution, the second granulation solution, and the pharmaceutical dosage form are free of citric acid. 
     
     
       60. The method of  claim 54 , wherein the lisinopril is present in the pharmaceutical dosage form in a range of 1 mg to 160 mg per unit dose. 
     
     
       61. The method of  claim 54 , where the simvastatin is present in the pharmaceutical dosage form in a range of 1 mg to 160 mg per unit dose. 
     
     
       62. The method of  claim 60 , wherein the pharmaceutical dosage form further comprises enteric coated aspirin or an enteric coated platelet inhibitor. 
     
     
       63. The method of  claim 62 , wherein the enteric coated platelet inhibitor is selected from the group consisting of clopidogrel, ticagrelor, prasugrel, dipyridamole, ticlopidine, eptifibatide, and combinations thereof. 
     
     
       64. The method of  claim 62 , wherein the enteric coated aspirin or the enteric coated platelet inhibitor is in a concentration of 25 mg to 325 mg per unit dose. 
     
     
       65. The method of  claim 62 , wherein the enteric coated aspirin is in a concentration of 81 mg per unit dose. 
     
     
       66. The method of  claim 54 , wherein the pharmaceutical dosage form is a capsule. 
     
     
       67. The method of  claim 66 , wherein the pharmaceutical dosage form further comprises enteric coated aspirin tablets or an enteric coated platelet inhibitor encased within the capsule. 
     
     
       68. The method of  claim 54 , wherein the pharmaceutical dosage form is a tablet. 
     
     
       69. The method of  claim 68 , wherein the tablet comprises a core and an immediate release outer layer, wherein the core of the tablet is enteric coated aspirin and the immediate release outer layer is comprised of the individual granules comprising the anti-hypertensive drug, the cholesterol-lowering drug, or a combination of the anti-hypertensive drug and the cholesterol-lowering drug. 
     
     
       70. The method of  claim 68 , wherein the tablet comprises a core and an immediate release outer layer, wherein the core of the tablet is an enteric coated platelet inhibitor and the immediate release outer layer is comprised of the individual granules comprising the anti-hypertensive drug, the cholesterol-lowering drug, or a combination of the anti-hypertensive drug and the cholesterol-lowering drug. 
     
     
       71. The method of  claim 54 , further comprising administering a single dosage of the pharmaceutical dosage form to an individual in need of an anti-hypertensive drug and a cholesterol-lowering drug once per 24-hour period.